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Am J Physiol Renal Physiol 297: F55-F62, 2009. First published April 29, 2009; doi:10.1152/ajprenal.00090.2009
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PPAR{gamma} agonists inhibit vasopressin-mediated anion transport in the MDCK-C7 cell line

Charity Nofziger,1 Kathleen K. Brown,2 Chari D. Smith,2 Wallace Harrington,2 David Murray,2 John Bisi,2 Thalia T. Ashton,2 Frank P. Maurio,2 Kameljit Kalsi,3 T. Aaron West,1 Deborah Baines,3 and Bonnie L. Blazer-Yost1

1Department of Biology, Indiana University-Purdue University at Indianapolis, Indianapolis, Indiana; 2GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina; and 3Ion Channels and Cell Signalling Research Centre, Division of Basic Medical Sciences, St. George's, University of London, London, United Kingdom

Submitted 16 February 2009 ; accepted in final form 21 April 2009

PPAR{gamma} agonists are synthetic ligands for the peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}). These agents have insulin-sensitizing properties but can cause fluid retention, thereby limiting their usefulness in patients at risk for cardiovascular disease. The side effect etiology is unknown, but the nature of presentation suggests modulation of renal salt and water homeostasis. In a well-characterized cell culture model of the principal cell type [Madin-Darby canine kidney (MDCK)-C7], PPAR{gamma} agonists inhibit vasopressin-stimulated Cl– secretion with agonist dose-response relationships that mirror receptor transactivation profiles. Analyses of the components of the vasopressin-stimulated intracellular signaling pathway indicated no PPAR{gamma} agonist-induced changes in basolateral membrane conductances, intracellular cAMP, protein kinase A, or total cellular adenine nucleotides. The PPAR{gamma} agonist-induced decrease in anion secretion is the result of decreased mRNA of the final effector in the pathway, the apically located cystic fibrosis transmembrane regulator (CFTR). These data showing that CFTR is a target for PPAR{gamma} agonists may provide new insights into the physiology of PPAR{gamma} agonist-induced fluid retention.

CFTR; edema; glitazones; thiazolidinediones; ENaC


Address for reprint requests and other correspondence: B. L. Blazer-Yost, Dept. of Biology, Indiana Univ.-Purdue Univ. at Indianapolis, Indianapolis, IN 46202 (e-mail: bblazer{at}iupui.edu)






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